Kang Shin-Chung, Brown David R, Whiteman Matthew, Li Ruliang, Pan Tao, Perry George, Wisniewski Thomas, Sy Man-Sun, Wong Boon-Seng
Institute of Pathology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
J Pathol. 2004 May;203(1):603-8. doi: 10.1002/path.1555.
Although the key event in the pathology of prion diseases is thought to be the conversion of cellular prion protein (PrP(C)) to the protease-resistant scrapie species termed PrP(Sc), the factors that contribute to neurodegeneration in scrapie-infected animals are poorly understood. One probable determinant could be when the accumulation of PrP(Sc) in infected brain overwhelms the ubiquitin-proteasome system and triggers the degenerative cascade. In the present study, it was found that in mouse brains infected with the ME7 scrapie strain, the level of ubiquitin protein conjugates increased significantly at approximately 144 days post-infection (pi) when clinical signs first become apparent. This elevation correlated with the detection of protease-resistant PrP(Sc) and a decline in two endopeptidase activities associated with proteasome function. However, ubiquitination of PrP was only detected at the terminal stage, 3 weeks after the development of clinical symptoms (approximately 165 days pi). These results suggest that ubiquitination of PrP is a late event phenomenon and this conjugation occurs after the formation of protease-resistant PrP(Sc). Whether this post-translational modification and the impairment of proteasome function are pivotal events in the pathogenesis of prion diseases remains to be determined.
尽管朊病毒疾病病理学中的关键事件被认为是细胞朊蛋白（PrP(C)）转变为被称为PrP(Sc)的蛋白酶抗性瘙痒病形式，但对瘙痒病感染动物中导致神经退行性变的因素却知之甚少。一个可能的决定因素可能是感染大脑中PrP(Sc)的积累超过泛素-蛋白酶体系统并触发退行性级联反应的时候。在本研究中，发现感染ME7瘙痒病株的小鼠大脑中，泛素蛋白缀合物水平在感染后约144天（pi）临床症状首次出现时显著升高。这种升高与蛋白酶抗性PrP(Sc)的检测以及与蛋白酶体功能相关的两种内肽酶活性的下降相关。然而，仅在临床症状出现3周后的末期阶段（约165天pi）检测到PrP的泛素化。这些结果表明PrP的泛素化是一种晚期事件现象，并且这种缀合发生在蛋白酶抗性PrP(Sc)形成之后。这种翻译后修饰和蛋白酶体功能损伤是否是朊病毒疾病发病机制中的关键事件仍有待确定。
